Cyclosporine augments renal but not systemic vascular reactivity.
Renal vasoconstriction and hypertension are major side effects of cyclosporine. We tested the acute effects of cyclosporine on renal and systemic vascular reactivity to norepinephrine, angiotensin II, and arginine vasopressin. Renal vascular reactivity was tested in anesthetized Sprague-Dawley rats with denervated kidneys. Renal blood flow was measured with an electromagnetic flow probe in response to graded intra-arterial infusions of vasoconstrictors before and after intravenous administration of cyclosporine. Cyclosporine augmented the decrease in renal blood flow and the increase in renal vascular resistance produced by intrarenal norepinephrine, angiotensin II, and arginine vasopressin. In these studies, systemic blood pressure did not change and cyclosporine caused no direct change in basal renal blood flow. In contrast, in conscious animals, cyclosporine did not increase the pressor response to intravenous norepinephrine or to angiotensin II. Rather, cyclosporine caused enhanced baroreflex slowing of heart rate and a decrease in the pressor response to both norepinephrine and angiotensin II. Even when the baroreceptor reflex was blocked by pentolinium, the pressor response to norepinephrine in cyclosporine-treated animals was diminished compared with vehicle-treated animals. Therefore, although cyclosporine augmented renal vasoconstriction in response to norepinephrine, angiotensin II, and arginine vasopressin, it did not acutely increase the systemic vascular response to these agents. Enhanced renal vascular responsiveness is an additional mechanism for cyclosporine-mediated renal vasoconstriction. Lack of enhanced peripheral vascular responsiveness suggests that hypertension is not likely to be due to direct effects on the systemic vasculature and is more likely to be a consequence of renal functional impairment.
Garr
M D
MD
Department of Medicine, University of Minnesota, Minneapolis 55455.
Paller
M S
MS
D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D001127:Arginine Vasopressin / Q000494:pharmacology; D001775:Blood Circulation / Q000187:drug effects*; D001794:Blood Pressure / Q000187:drug effects; D001808:Blood Vessels / Q000187:drug effects / Q000502:physiology; D003524:Cyclosporins / Q000494:pharmacology*; D006439:Hemodynamics / Q000187:drug effects; D008297:Male; D009638:Norepinephrine / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D012079:Renal Circulation / Q000187:drug effects*; D014661:Vasoconstriction
D003524:Cyclosporins; D000804:Angiotensin II; D001127:Arginine Vasopressin; D009638:Norepinephrine